Catalyst-Dependent Asymmetric Dearomative and Desymmetrizative Higher-Order [8 + 2] Cycloaddition of Indolizines with Maleimides toward the Atroposelective Synthesis of Cyclazines

The dearomatization of indolizines via higher-order [8 + 2] cycloadditions offers a direct route to the relevant core of cyclazines. However, surpassing the thermodynamic pathway that led to Friedel–Crafts-type conjugate addition adducts under catalytic conditions was never accomplished. Herein, we described that chiral phosphoric acids (CPAs) were able to favor the dearomative and desymmetrizative higher-order cycloaddition (HOC) between indolizines and maleimides, leading to atropoisomeric endo-cyclazines with high enantioselectivities (up to 98:2 e.r.). Theoretical calculations supported a kinetically favored stepwise cycloaddition pathway over the expected conjugated addition one. Notably, the latter was favored when the model phosphoric acid organocatalyst diphenyl phosphate was used instead of CPAs. Furthermore, a new mechanism for a key isomerization step, previously suggested as a sigmatropic event, in which the catalyst serves as a proton shuttle, was proposed.